Mode of Action of Chlorinated Ethylenes on the Expression of Rat Cytochrome P450 forms and Specificity in the Metabolic Activation of CEs by CYPs

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Chlorinated ethylenes (CEs) including tetrachioroethylene (PCE), trichloroethylene (TCE) and 1,1-dichioroethylene (DCE) were comparatively evaluated for their effects on the expression of cytochrome P450 (CYP) forms of subfamilies 1A, 2B, 2E and 3A as well as their relative suitability as substrates of these CYPs. The magnitudes of inhibition of the enzyme activities were as follows in descending order: 1,1-DCE > TCE > PCE against hepatic CYPs and PCE > 1,1-DCE > TCE against pulmonary CYP2B1. These organ-specific profiles in the sensitivities to the adverse effects of CEs were partly attributable to the differential expression patterns of CYP forms by which they were metabolically activated. The expression of hepatic and pulmonary CYP2B mRNA was severely suppressed in the presence of 1,1-DCE during the entire observation period until 30 hr after the CE-treatment, in marked contrast to the temporarily enhanced expression at 6 hr followed by a moderate suppression in the cases of PCE and TCE with the trough values being observed at 18 hr. In addition to CYP2B, 1,1-DCE in advance of the transcriptional stage, when simultaneously treated with phenobarbital, also exclusively suppressed CYP2E1. These general suppressive effects of 1,1-DCE on the expression of divergent CYP mRNAs in vivo resembled the published findings in primary cultured hepatocytes treated with inflammatory cytokines such as IL-1β, TNF-α and IL-6, implying the highly inflammatory nature of 1,1-DCE.
公益社団法人日本薬学会の論文
2002-06-01

Mode of Action of Chlorinated Ethylenes on the Expression of Rat Cytochrome P450 forms and Specificity in the Metabolic Activation of CEs by CYPs

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